Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction.
Cardiac dysfunction following acute myocardial infarction is a major cause of death in the world and there is a compelling need for new therapeutic strategies. In this report we demonstrate that a direct cardiac injection of drug-loaded microparticles, formulated from the polymer poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK), improves cardiac function following myocardial infarction. Drug-delivery vehicles have great potential to improve the treatment of cardiac dysfunction by sustaining high concentrations of therapeutics within the damaged myocardium. PCADK is unique among currently used polymers in drug delivery in that its hydrolysis generates neutral degradation products. We show here that PCADK causes minimal tissue inflammatory response, thus enabling PCADK for the treatment of inflammatory diseases, such as cardiac dysfunction. PCADK holds great promise for treating myocardial infarction and other inflammatory diseases given its neutral, biocompatible degradation products and its ability to deliver a wide range of therapeutics.
Sy
Jay C
JC
Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA.
Seshadri
Gokulakrishnan
G
Yang
Stephen C
SC
Brown
Milton
M
Oh
Teresa
T
Dikalov
Sergey
S
Murthy
Niren
N
Davis
Michael E
ME
D000818:Animals; D002460:Cell Line; D003692:Delayed-Action Preparations; D007093:Imidazoles / Q000008:administration & dosage*; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D010766:Phosphorylation; D011108:Polymers; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D003692:Delayed-Action Preparations; D007093:Imidazoles; D011108:Polymers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; C517410:poly(cyclohexane-1,4-diyl acetone dimethylene ketal); D013481:Superoxides; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063